Illuminating the Mechanics of Life

“Seeing is believing” is the guiding principle in the laboratory of Bo Huang, PhD, a professor in the UCSF Department of Pharmaceutical Chemistry. Collaborators from diverse disciplines come to the lab with some of the thorniest questions about life’s cellular mechanisms. Understanding these intricate processes is crucial to treating disease. But they often are so complex – involving hundreds of tiny molecules – that researchers can’t visualize them with standard microscopes, relying instead on inference from indirect measurements. 

Huang’s team takes a more direct approach. “Our answer is to build a microscopy tool to reveal what is actually happening,” he says. Among the team’s innovations are technologies that “paint” molecules with fluorescent tags and generate super-resolution images, allowing researches to see up close what’s going on in a cell or tissue. 

More often than not, the results defy expectations. Take, for example, a recent request from oncologist Trever Bivona, MD, PhD, an associate professor in the UCSF Division of Hematology and Oncology and the UCSF Helen Diller Family Comprehensive Cancer Center. Bivona approached Huang to help figure out how a mutation in a particular protein signals the nonstop cell growth endemic to cancer. To map these signals, Huang used the revolutionary gene-editing tool known as CRISPR-Cas9 to tag the mutated proteins so he could track their behavior. 

What he saw surprised everyone. Typically, growth signals originate on a cell’s membrane. But Huang found that in this case, the signals came from clusters of mutated proteins inside the cell. This unexpected finding could provide a new route for shutting the signals down, potentially leading to new cancer treatments. 
  
Meanwhile, Huang’s lab is pioneering other applications of CRISPR-Cas9 to expand what scientists and doctors are able to see under the microscope. In work published in the prestigious journal Cell, for instance, Huang and his colleagues debuted a technique that uses CRISPR-Cas9 to tag individual genes. This innovation is a boon to researchers trying to decode the mysteries of the human genome.  

It could only have happened at UCSF,” Huang says. “It took people who know cell biology, biochemistry, protein engineering, gene editing, and microscope construction – and who are ready and willing to collaborate.

In fact, the entire project – from idea generation to experiments – took all of one week. “It happened so fast that there was no way for me to apply for [government] grants,” Huang says. Luckily, funding from the Sandler Family Foundation – granted through the UCSF Program for Breakthrough Biomedical Research (PBBR) – and follow-up funding from the Keck Foundation kept the project going.  

“Philanthropy made it happen,” Huang says.